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The role of NOS2A -954G/C and vascular endothelial growth factor +936C/T polymorphisms in type 2 diabetes mellitus and diabetic nonproliferative retinopathy risk management.

ABSTRACT: Type 2 diabetes mellitus (T2DM) remains one of the major health problems in Europe. Retinopathy is one of the major causes of morbidity in T2DM, strongly influencing the evolution and prognosis of these patients. In the last 2 decades, several studies have been conducted to identify the possible genetic susceptibility factors involved in the pathogenesis of the disease. However, there is little data related to the involvement of vascular endothelial growth factor (VEGF) and nitric oxide synthase (NOS) gene polymorphisms in the T2DM Caucasian population. The objective of this study was to identify a possible connection between NOS2A -954G/C (rs2297518) and VEGF +936C/T (rs3025039) polymorphisms and the risk of developing T2DM and nonproliferative diabetic retinopathy in a Caucasian population group. We investigated 200 patients diagnosed with T2DM and 208 controls. Genotypes were determined by multiplex polymerase chain reaction-restriction fragment length polymorphism. Statistical and comparative analyses (Fisher's exact test) for dominant and recessive models of NOS2A -954G/C and VEGF +936C/T polymorphisms revealed an increased risk of T2DM (? (2)=8.14, phi =0.141, P=0.004, odds ratio [OR] =2.795, 95% confidence interval [CI] =1.347-5.801; ? (2)=18.814, phi =0.215, P<0.001, OR =2.59, 95% CI =1.675-4.006, respectively). Also, comparative analysis for the recessive model (using Pearson's chi-square test [? (2)] and the phi coefficient [phi]) reveals that the variant CC genotype of NOS2A gene is more frequently associated with T2DM without retinopathy (? (2)=3.835, phi =-0.138, P=0.05, OR =0.447, 95% CI =0.197-1.015). In conclusion, the results of the study place VEGF +936C/T polymorphisms among the genetic risk factor for T2DM, whereas NOS2A -954G/C polymorphisms act like a protective individual factor for nonproliferative retinopathy.

SUBMITTER: Porojan MD

PROVIDER: S-EPMC4669928 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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The role of NOS2A -954G/C and vascular endothelial growth factor +936C/T polymorphisms in type 2 diabetes mellitus and diabetic nonproliferative retinopathy risk management.

Porojan Mihai Dumitru MD Cătană Andreea A Popp Radu A RA Dumitrascu Dan L DL Bala Cornelia C

Therapeutics and clinical risk management 20151127

Type 2 diabetes mellitus (T2DM) remains one of the major health problems in Europe. Retinopathy is one of the major causes of morbidity in T2DM, strongly influencing the evolution and prognosis of these patients. In the last 2 decades, several studies have been conducted to identify the possible genetic susceptibility factors involved in the pathogenesis of the disease. However, there is little data related to the involvement of vascular endothelial growth factor (VEGF) and nitric oxide synthase ...[more]

PMID: 26664124

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Project description:PurposeTo determine risk factors that affect nonproliferative diabetic retinopathy (NPDR) progression and establish a predictive model to estimate the probability of and time to progression in NPDR. Patients and Methods. Charts of diabetic patients who received an initial eye exam between 2010 and 2017 at our county hospital were included. Patients with proliferative diabetic retinopathy (PDR), fewer than 2 years of follow-up, or fewer than 3 clinic visits were excluded. Demographics and baseline systemic and ocular characteristics were recorded. Follow-up mean annual HbA1c and blood pressure, best-corrected visual acuity, and the number of antivascular endothelial growth factor treatments were recorded. Stage and date of progression were recorded. A 5-state nonhomogeneous continuous-time Markov chain with a backward elimination model was used to identify risk factors and estimate their effects on progression.ResultsTwo hundred thirty patients were included. Initially, 65 eyes (28.3%) had no retinopathy; 73 (31.7%) mild NPDR; 60 (26.1%) moderate NPDR; and 32 (13.9%) severe NPDR. Patients were followed for a mean of 5.8 years (±2.0 years; range 2.1-9.4 years). 164 (71.3%) eyes progressed during the follow-up. Time-independent risk factors affecting progression rate were age (hazard ratio (HR) = 0.99, P=0.047), duration of diabetes (HR = 1.02, P=0.018), and Hispanic ethnicity (HR = 1.31, P=0.068). Mean sojourn times at mean age, duration of diabetes, and annual HbA1c for a non-Hispanic patient were estimated to be 3.03 (±0.97), 4.63 (±1.21), 6.18 (±1.45), and 4.85 (±1.25) years for no retinopathy, mild NPDR, moderate NPDR, and severe NPDR, respectively. Each 1% increase in HbA1c annually diminished sojourn times by 15%, 10%, 7%, and 10% for no retinopathy, mild NPDR, moderate NPDR, and severe NPDR, respectively.ConclusionHbA1c level is a significant modifiable risk factor in controlling the progression of DR. The proposed model could be used to predict the time and rate of progression based on an individual's risk factors. A prospective multicenter study should be conducted to further validate our model.

Project description:Purpose:To assess the relationship between metformin use and the severity of diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM) and to investigate the effect of metformin dosage on reducing the incidence of DR. Methods:The study population included patients with newly diagnosed T2DM, who were aged ?20 years and prescribed with antidiabetic drug therapy lasting ?90 days, as identified using the National Health Insurance Research Database between 2000 and 2012. We matched metformin users and nonusers by a propensity score. Cox proportional hazard regression analyses were used to compute and compare the risk of developing nonproliferative diabetic retinopathy (NPDR) in metformin users and nonusers. Results:Overall, 10,044 T2DM patients were enrolled. Metformin treatment was associated with a lower risk of NPDR (aHR 0.76, 95% CI 0.68-0.87) and sight-threatening diabetic retinopathy (STDR, aHR 0.29, 95% CI 0.19-0.45); however, the reduction in risk was borderline significant for STDR progression among NPDR patients (aHR 0.54, 95% CI 0.28-1.01). Combination therapy of metformin and DPP-4i exhibited a stronger but inverse relationship with NPDR development (aHR 0.32, 95% CI 0.25-0.41), especially at early (<3 months) stages of metformin prescription. These inverse relationships were also evident at different metformin doses and in adapted Diabetes Complications Severity Index scores (aDCSI). Moreover, combination therapy of metformin with sulfonylureas was associated with an increased risk of NPDR. Conclusion:Metformin treatment in patients with T2DM was associated with a reduced risk of NPDR, and a potential trend was found for a reduced STDR risk in patients who had previously been diagnosed with NPDR. Combining metformin with DPP-4i seemingly had a significantly beneficial effect against NPDR risk, particularly when aDCSI scores were low, and when metformin was prescribed early after T2DM diagnosis. These results may recommend metformin for early treatment of T2DM.

Dataset Information

The role of NOS2A -954G/C and vascular endothelial growth factor +936C/T polymorphisms in type 2 diabetes mellitus and diabetic nonproliferative retinopathy risk management.

Publications

The role of NOS2A -954G/C and vascular endothelial growth factor +936C/T polymorphisms in type 2 diabetes mellitus and diabetic nonproliferative retinopathy risk management.

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